Targeting Malignant Gliomas with Dual Biomarker Targeted Immunotherapy and Nano-Irradiation

Akiva Mintz M.D., Ph.D.

Wake Forest University

Funded in September, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Targeted immunotherapy and radiation combination therapy holds promise against malignant brain tumors

The research goal is to activate the immune system to precisely target malignant brain glioma cells while simultaneously delivering radiation to the infiltrating tumor without harming adjacent normal brain cells.


The malignant cells of high grade glioblastomas that infiltrate healthy brain tissue are currently outside the reach of standard brain tumor therapies and are responsible for the inevitable recurrence of this cancer that kills within a year or two. The investigators will target tumor specific molecules that are found on the surface of more than 95 percent of glioblastoma cells but not on normal brain cells. These “biomarkers” provide the potential for activating immune cells to precisely target tumor cells while sparing adjacent normal tissue. They have developed a molecular scaffolding designed to recognize the biomarkers on tumor cells. Moreover, they can attach ultra short-range (nanometer) radioactivity to this molecule.


The researchers hypothesize, therefore, that they can precisely and simultaneously target glioblastoma cells with immunotherapy augmented by radiation while sparing nearby healthy brain cells. Furthermore, they hypothesize, the anti-tumor immune response that is elicited can protect against development of additional tumors. After producing the molecular scaffolding and attaching ultra short-range radioactivity to it, they will conduct laboratory experiments to see if the molecule attaches to glioblastoma cells—including those from tumors that had been surgically removed from patients and those from a glioblastoma cell line—but not to normal brain cells. Thereafter, they will test this experimental treatment on mice that have been implanted with cells from patients’ surgically removed tumors.


Significance: If successful, this experimental combination of immunotherapy and radiation treatment ultimately could be used in patients to eradicate infiltrating glioblastoma cells and prevent this deadly tumor’s recurrence while producing no collateral damage to normal brain tissues.

ABSTRACT

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Targeting Malignant Gliomas with Dual Biomarker Targeted Immunotherapy and Nano-Irradiation

High grade malignant gliomas are the leading cause of primary brain cancer deaths, afflicting close to 20,000 patients annually in the United States alone. Targeting tumor-specific molecular biomarkers with immunotherapy and/or immune-targeted irradiation offers the potential to specifically eradicate infiltrating tumor cells but not harm the surrounding normal brain tissue. Therefore, our overall goal is to create a targeted molecular scaffolding that can effectively and precisely activate the immune system against malignant glioma cells and simultaneously deliver large amounts of molecular targeted nano-irradiation to infiltrating tumor cells without harming adjacent normal brain. The central hypothesis behind the proposed research that we can activate an immune response and deliver ultra-short range cytotoxic radionclides via a novel recombinant carrier that we invented to target over 95% of stage IV malignant gliomas. We will accomplish our objectives via two specific aims. In specific aim 1, we will produce, radiolabel and characterize the structure/function of our molecular scaffolding and examine its affinity towards a wide range of fresh-frozen glioma specimens, normal brain and malignant glioma cell lines. In specific aim 2, we will assess the in vitro and in vivo cytotoxicity of our molecular scaffolding (unlabeled or radiolabeled) against various malignant glioma cell lines as well as in human malignant glioma xenograph orthotopic mouse models. We will additionally examine for long term immuno-protective effects of our radiolabeled scaffolding by re-challenging cured mice with additional tumor cells.


Our expectations are that at the conclusion of the proposed work, we will have created a clinically relevant anti-tumor agent with potential to eradicate infiltrating tumor cells and hence prevent recurrence while causing no collateral damage to normal brain. In addition, we anticipate our system will be an ideal scaffolding to safely deliver other therapeutics to infiltrative malignant glioma cells that are currently outside the reach of standard therapy and responsible for the inevitable recurrence of malignant high grade gliomas.

INVESTIGATOR BIOGRAPHIES

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Akiva Mintz M.D., Ph.D.

The PI of this proposal is an Assistant Professor at Wake Forest University Health Sciences in the Departments of Neurosurgery (Brain Tumor Center of Excellence; BTCOE) and Radiology. In the BTCOE, he leads the biomolecular imaging group, where his interests include delivering diagnostic and therapeutic radionuclides specifically to malignancy via tumor-restricted biomarkers. In addition, Dr. Mintz actively practices clinically nuclear medicine, in which he is board certified. He completed his M.D. and Ph.D. at the Pennsylvania State College of Medicine, followed by his training in clinical nuclear medicine, as well as an NIH-sponsored multimodality molecular imaging fellowship, at the University of Pennsylvania.